4gl7: Difference between revisions
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==Structure of human placental aromatase complexed with designed inhibitor HDDG046 (compound 5)== | |||
<StructureSection load='4gl7' size='340' side='right' caption='[[4gl7]], [[Resolution|resolution]] 3.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4gl7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GL7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GL7 FirstGlance]. <br> | |||
==Disease== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0XJ:(6ALPHA,8ALPHA)-6-(PENT-2-YN-1-YLOXY)ANDROSTA-1,4-DIENE-3,17-DIONE'>0XJ</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene></td></tr> | ||
[[http://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN]] Defects in CYP19A1 are a cause of aromatase excess syndrome (AEXS) [MIM:[http://omim.org/entry/139300 139300]]; also known as familial gynecomastia. AEXS is characterized by an estrogen excess due to an increased aromatase activity. Defects in CYP19A1 are the cause of aromatase deficiency (AROD) [MIM:[http://omim.org/entry/613546 613546]]. AROD is a rare disease in which fetal androgens are not converted into estrogens due to placental aromatase deficiency. Thus, pregnant women exhibit a hirsutism, which spontaneously resolves after post-partum. At birth, female babies present with pseudohermaphroditism due to virilization of extern genital organs. In adult females, manifestations include delay of puberty, breast hypoplasia and primary amenorrhoea with multicystic ovaries.<ref>PMID:8265607</ref><ref>PMID:8530621</ref><ref>PMID:9211678</ref> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3eqm|3eqm]], [[3s79|3s79]], [[3s7s|3s7s]], [[4gl5|4gl5]]</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Unspecific_monooxygenase Unspecific monooxygenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.14.1 1.14.14.1] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4gl7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gl7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gl7 RCSB], [http://www.ebi.ac.uk/pdbsum/4gl7 PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN]] Defects in CYP19A1 are a cause of aromatase excess syndrome (AEXS) [MIM:[http://omim.org/entry/139300 139300]]; also known as familial gynecomastia. AEXS is characterized by an estrogen excess due to an increased aromatase activity. Defects in CYP19A1 are the cause of aromatase deficiency (AROD) [MIM:[http://omim.org/entry/613546 613546]]. AROD is a rare disease in which fetal androgens are not converted into estrogens due to placental aromatase deficiency. Thus, pregnant women exhibit a hirsutism, which spontaneously resolves after post-partum. At birth, female babies present with pseudohermaphroditism due to virilization of extern genital organs. In adult females, manifestations include delay of puberty, breast hypoplasia and primary amenorrhoea with multicystic ovaries.<ref>PMID:8265607</ref> <ref>PMID:8530621</ref> <ref>PMID:9211678</ref> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/CP19A_HUMAN CP19A_HUMAN]] Catalyzes the formation of aromatic C18 estrogens from C19 androgens. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylidene-androsta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilizing the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC50s in the nM range. Anti-proliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC50s better than 1nM, exceeding exemestane. X-ray structures of aromatase-complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme-substrate/exemestane complexes. The observed structure-activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs. | |||
Novel Aromatase Inhibitors By Structure-Guided Design.,Ghosh D, Lo J, Xi J, Hubbell S, Egbuta C, Jiang W, An J, Morton D, Valette D, Griswold J, Davies HM J Med Chem. 2012 Sep 5. PMID:22951074<ref>PMID:22951074</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Cytochrome P450|Cytochrome P450]] | *[[Cytochrome P450|Cytochrome P450]] | ||
== References == | |||
== | <references/> | ||
<references | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Unspecific monooxygenase]] | [[Category: Unspecific monooxygenase]] | ||
[[Category: Ghosh, D | [[Category: Ghosh, D]] | ||
[[Category: Cytochrome p450 reductase]] | [[Category: Cytochrome p450 reductase]] | ||
[[Category: Er membrane]] | [[Category: Er membrane]] | ||
Revision as of 14:15, 21 December 2014
Structure of human placental aromatase complexed with designed inhibitor HDDG046 (compound 5)Structure of human placental aromatase complexed with designed inhibitor HDDG046 (compound 5)
Structural highlights
Disease[CP19A_HUMAN] Defects in CYP19A1 are a cause of aromatase excess syndrome (AEXS) [MIM:139300]; also known as familial gynecomastia. AEXS is characterized by an estrogen excess due to an increased aromatase activity. Defects in CYP19A1 are the cause of aromatase deficiency (AROD) [MIM:613546]. AROD is a rare disease in which fetal androgens are not converted into estrogens due to placental aromatase deficiency. Thus, pregnant women exhibit a hirsutism, which spontaneously resolves after post-partum. At birth, female babies present with pseudohermaphroditism due to virilization of extern genital organs. In adult females, manifestations include delay of puberty, breast hypoplasia and primary amenorrhoea with multicystic ovaries.[1] [2] [3] Function[CP19A_HUMAN] Catalyzes the formation of aromatic C18 estrogens from C19 androgens. Publication Abstract from PubMedHuman cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylidene-androsta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilizing the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC50s in the nM range. Anti-proliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC50s better than 1nM, exceeding exemestane. X-ray structures of aromatase-complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme-substrate/exemestane complexes. The observed structure-activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs. Novel Aromatase Inhibitors By Structure-Guided Design.,Ghosh D, Lo J, Xi J, Hubbell S, Egbuta C, Jiang W, An J, Morton D, Valette D, Griswold J, Davies HM J Med Chem. 2012 Sep 5. PMID:22951074[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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